Ischemic stroke is caused by cerebral blood flow (CBF) inadequate to allow brain tissue survival. It is known from humans treated with tissue plasminogen activator that ischemic tissue can be salvaged from infarction by thrombolytic CBF restoration. This improves outcome. Thus, improved CBF is a therapeutic target. Various compounds, known to either donate nitric oxide (NO) or upregulate eNOS expression (e.g., simvastatin), increase CBF in ischemic tissue and improve experimental stroke outcome. While the common mechanism appears to be increased NO bioactivity and vasodilation, most such compounds are impractical as stroke therapeutics because of either delayed onset of action, or lack of specificity for ischemic tissue causing the dose to be limited by systemic hypotension. A novel mechanism for selective vasodilation is allosterically- modulated delivery of hemoglobin borne nitric oxide bioactivity. S-nitrosylated hemoglobin (SNO-Hb) is stable in the oxygenated form but unstable when O2 is offloaded. This offers opportunity to selectively increase NO bioactivity along PO2 gradients between blood and ischemic tissue while maintaining hemodynamic stability. Ethyl nitrite is an inhaled gas that markedly increases SNO-Hb. Ethyl nitrite decreases severity of pulmonary artery hypertension in adult and infant humans, and selectively decreases end-organ ischemia in models of pneumoperitoneum, cerebral vasospasm and free muscle flaps and has no effect on blood pressure. We propose projects to investigate effects of modulating SNO-Hb on cerebral ischemic outcome. Using an established, physiologically-controlled rat middle cerebral artery occlusion (MCAO) model, we will 1) Define acute effects of 20 ppm ethyl nitrite inhalation on absolute CBF during and after filament MCAO and measure amount of tissue at risk for cerebral infarction as a function of the fraction of inspired oxygen (Fi02), 2) Define ethyl nitrite efficacy in a long-term outcome rat model of permanent focal ischemic stroke as a function of Fi02, and 3) Define ethyl nitrite efficacy in a long-term outcome rat model of temporary focal ischemic stroke as a function of Fi02. Preliminary studies in this model have shown that treatment with ethyl nitrite either during or after transient focal ischemia causes rapid and reversible increases in laser Doppler CBF. Preliminary data indicates lack of an adverse effect on platelet function. We, therefore, predict improved outcome in both temporary and permanent MCAO.
The goal of this project is to determine the effectiveness of an inhaled gas, ethyl nitrite, in improving blood flow during an experimental stroke in rats. We have evidence that indicates that ethyl nitrite will selectively improve blood flow to the part of the brain that is experiencing a stroke, but that will do so with little or no effect on blood flow to other parts of the body. We will then examine whether this effect is important in reducing the amount of tissue damage and neurologic impairment caused by the stroke.
|Sheng, Huaxin; Reynolds, James D; Auten, Richard L et al. (2011) Pharmacologically augmented S-nitrosylated hemoglobin improves recovery from murine subarachnoid hemorrhage. Stroke 42:471-6|
|Wang, Zhengfeng; Yang, Wei; Britz, Gavin W et al. (2010) Development of a simplified spinal cord ischemia model in mice. J Neurosci Methods 189:246-51|